This invention relates to droloxifene pharmaceutical compositions.
Droloxifene is disclosed in U.S. Pat. No. 5,047,431 (the disclosure of which is hereby incorporated by reference) as an anti-tumor agent, particularly for treatment of cancer of the breast. Droloxifene is also useful for the relief of bone diseases caused by the deficiency of estrogen or the like, which are often observed in women after menopause or those with the ovaries removed (U.S. Pat. No. 5,254,594 (the disclosure of which is hereby incorporated by reference)).
Formulation of pharmaceutical dosage forms is frequently hampered by poor aqueous solubility and/or stability of the drug of interest, which in turn can severely limit its therapeutic application. Conversely, increasing drug solubility and stability through appropriate formulation can lead to increased therapeutic efficiency of the drug. Various methods have been used to increase the solubility and stability of drugs such as the use of organic solvents, emulsions, liposomes and micelles, chemical modifications, and complexation of drugs with appropriate complexing agents such as cyclodextrins.
Cyclodextrins, sometimes referred to as Schardinger's dextrins, were first isolated by Villiers in 1891 as a digest of Bacillus amylobacter on potato starch. The foundations of cyclodextrin chemistry were laid down by Schardinger in the period 1903-1911. Until 1970, however, only small amounts of cyclodextrins could be produced in the laboratory and the high production cost prevented the usage of cyclodextrins in industry. In recent years, dramatic improvements in cyclodextrin production and purification have been achieved and cydodextrins have become much less expensive, thereby making the industrial application of cyclodextrins possible.
Cyclodextrins are capable of forming inclusion complexes with a wide variety of hydrophobic molecules by taking up a whole molecule (a "guest molecule"), or some part of it, into the void cavity. The stability of the resulting complex depends on how well the guest molecule fits into the cyclodextrin cavity.
The following published patents describe the use of cyclodextrins to stabilize pharmaceutical compounds:
WO 9311757; PA0 WO 9002141; PA0 WO 9416733; and PA0 EP 658348. PA0 Hirayama, F et al. J Pharm Sci, 81, 817, (1992); PA0 Duveneck, G et al. J Phys Chem, 93, 7166, (1989); and PA0 Bortolus, P et al. J Phys Chem, 91, 5046 (1987). PA0 Loftsson, T. et al. J. Pharm Sci, 85, 1017 (1996); PA0 Helm, H et al. Eur Pharm Sci, 3, 195 (1995); PA0 Muller, B W et al. In: Proc, 4.sup.th Int. Symp. Cyclodextrins, 369-82 (1988); PA0 Pop, E et al. Pharm Res., 8, 1044 (1991); PA0 Gorecka, B et al. Int J Pharm, 125, 55 (1995); and PA0 Brewster, M et al. Pharm. Res, 8, 792 (1991).
The following articles describe the use of cyclodextrins to stabilize compounds which undergo an isomerization reaction:
The following are general articles on the solubilization and stabilization of pharmaceutical compounds using cyclodextrins:
The following article reviews the methods of preparation of compound-cyclodextrin complexes:
Hirayama, F. et al. In Cyclodextrins and their Industrial Uses; Duchene, D., Ed.; Editions de Sante: Paris 1987; Chapter 4, pp131-172.
Although cyclodextrins have been used to increase the solubility, dissolution rate and/or stability of a great many compounds, it is also known there are many compounds for which cyclodextrin complexation either is not possible or yields no advantages (J. Szejtli, Cyclodextrins in Drug Formulations: Part II, Pharmaceutical Technology, 24-38, August, 1991).